OBJECTIVE: The aim of the present paper
is to review the various aspects of refractory schizophrenia regarding issues
such as definitions, clinical aspects, psychobiological correlates, pharmacological
and non-pharmacological treatment options and predictors of treatment response.METHOD: Medline search as well as articles of the authors. RESULTS AND CONCLUSIONS: Refractory schizophrenia affects at least one
third of patients with schizophrenia and the best evidence shows that is monotherapy
with clozapine remains the mainstay for the treatment of such condition. Antipsychotic
polipharmacy is not supported by current evidence and recent clinical trials
have shown that clozapine augmentation with antipsychotics has no benefit over
placebo.

What is refractory schizophrenia? In so far as
schizophrenia is, by definition, a chronic disease in which 80-90% of patients
manifest social or occupational dysfunction compared to what might have been
expected of them from their premorbid or familial level of function, it is difficult
to draw the line between treatment responsive and treatment refractory schizophrenia.1
Chronicity is frequently taken as a synonym of refractoriness but that does
not help to illuminate the concept. There is clear distinction between chronicity
and refractoriness in other areas of medicine since there are various chronic
diseases, as for example diabetes or hypertension which, despite their chronicity,
do, in fact, respond to treatment, with patients achieving stability, by taking
hypoglycemic agents or antihypertensives throughout their lives.

Sometimes the term refractory schizophrenia (RS)
or "treatment-resistant schizophrenia (TRS)" is incorrectly applied
to patients who are symptomatic because of lack of compliance. This is better
thought of as the patient is resisting treatment rather than that the illness
itself is resistant to the expected response to treatment.

1. Clinical aspects of RS

Various cohort studies indicate that 20-30% of
patients with schizophrenia meet criteria for RS. Although higher rates have
been reported, it is likely that this represents an usual clustering of refractory
cases or inadequate treatment strategies with regard to dose or duration of
treatment.2

Meltzer et al., comparing TRS-patients versus
non-RS patients reported that the RS patients had, on average, a 2-year earlier
age of onset, and were more likely to be males.3 Similarly, Henna
and Elkis observed that, in terms of gender distribution, patients with RS were
predominantly male, experienced a higher number of hospitalizations, and had
an age of onset of around 17 years for the disorder, as compared to those without
RS (around 20 years).4 Other features reported to be associated with
RS are a greater number of episodes of illness and hospitalizations, and a history
of substance abuse. Because they are refractory to ordinary doses of typical
neuroleptic drugs, RS patients will often have been treated with much higher
than normal doses of medication and polypharmacy.

In terms of the psychopathology, Lindenmayer
et al., using the Positive and Negative Syndrome Scale (PANSS), evaluated 157
patients with RS and found that the factor structure was no different from non
RS patients, i.e. positive, negative, excitement, cognitive and depressive clusters.5
The same type of results were obtained with the Brief Psychiatric Rating Scale
(BPRS), where McMahon et al. compared the structure of the scale in 1,074 patients
with schizophrenia intolerant to antipsychotics, of whom 197 met criteria for
observed through Confirmatory Factor Analysis that 13 of the 18 items of the
BPRS loaded into four factors: reality distortion, disorganization, negative,
anxiety/depression in both groups.6

Similarly, we analyzed data from an homogenous
population of 96 patients narrowly defined as having RS and assessed by an anchored
version of the BPRS and found also four dimensions: negative/disorganization,
excitement, positive and depression.7

2. Current definitions of RS

For most investigators, persistent moderate to
severe positive symptoms is the core feature of RS.8 Some believe
that other dimensions of schizophrenia should be included, such as negative
and cognitive symptoms, as well as the inability to return to the best premorbid
level of functioning.2

In this concept, RS is multidimensional which
implies that a simple dichotomous (yes or no) definition is inadequate. Some
authors tried to construct one-dimensional definitions based upon global symptom
reduction9 or bi-dimensional, taking into account social adaptation,
as well as symptom reduction10 Brenner et al. conceived RS as a continuum
of resistance to refractoriness and developed a scale for measurement based
on psychopathology and social adaptation.11

The operational criterion most widely used for
the definition of RS in clinical studies is that of Kane and Meltzer used for
the study that introduced clozapine to the therapeutic armamentarium for schizophrenia.12
Kane and Meltzer criteria are three-dimensional: 1) Historic: a history
of total or partial lack of response to previous treatment using two antipsychotics
at adequate doses and periods; 2) Actual (Severity of Symptoms): the
patient must present a certain level of psychopathologic severity as assessed
by the BPRS and the Global Clinical Impression (GCI) and 3) Confirmatory,
i.e. following treatment with one or more antipsychotic drug, the patient must
show minimal improvement in symptomatology (BPRS and CGI) as compared to pretreatment
levels of psychopathology.

3. Definitions of RS based on algorithms

Guidelines for the treatment of schizophrenia
such as the American Psychiatric Association13 or algorithms such
as the Texas Medication Algorithm Project (TMAP)14 have established
that after the failure of two or three treatments on atypical antipsychotics,
the patient should be considered as having RS. This has been considered to make
the patient a good candidate for treatment with clozapine, the only drug approved
for RS.

The most recent algorithm, the Schizophrenia
Algorithm of the International Psychopharmacology Algorithm Project (IPAP) (www.ipap.org)
defines that a patient is considered to be refractory if he or she failed to
respond to two trials of 4 to 6 weeks of duration of monotherapy with two different
SGA (or two trials with a FGA, if SGAs are not available). In this case the
patient is considered to have RS and is eligible for treatment with clozapine,
at doses ranging from 300 mg/day up to 900 mg/day (see Figure
1). Patients who are so intolerant of treatment with any antipsychotic drug
available that they cannot have an adequate trial of any drug of this class
would be considered antipsychotic intolerant, not RS.

4. Clinical and psychobiological correlates of RS

Sheitman and Lieberman15 hypothesize
that the evolution of RS occurs in three stages: 1) cortical pathology and deficient
neuromodulatory capacity; 2) neurochemical sensitization; and 3) neurotoxicity.
RS have been related to neurodevelopmental brain abnormalities such as the presence
of ventricular enlargement, which have a negative correlation with treatment
response with antipsychotics. Reviews of retrospective studies suggest that
ventricular enlargement is related to poor outcome, whereas in prospective studies
such abnormality is associated with response to conventional antipsychotics,
while cortical atrophy possibly mediates the effects of atypical neuroleptics.16

There are few other neurobiological correlates
of RS such as plasma homovanillic acid, which is decreased in first episode
patients or altered T- cell functions, as well as alterations of inflammatory
process mediated by interleukins that do not respond to treatment.17
The importance of genetic factors that govern response to treatment will be
discussed subsequently.

5. Treatment of RS

1) Clozapine

Meta-analyses of controlled trials and systematic
reviews involving patients with RS are consistent in showing that clozapine,
when compared to other SGA, is the treatment of choice for RS.18-21

There are three meta-analyses of the clozapine
vs FGA18 and FGA vs SGA.19,20 One of the studies which
favorably compared clozapine to FGA and found an effect size of 0.44 in favor
of clozapine, nevertheless pointed out that many other studies that found these
same results suffered from methodological bias, including the heterogeneity
and duration of the studies, the initial psychopathology of patients, the year
of publication and sponsorship.20

The meta-analysis of the Cochrane Center included
only eight studies that compared Clozapine with SGA. Clozapine showed a trend
to be more effective in terms of improving positive symptoms but not negative
symptoms, while other outcome variables such as relapse rates or global improvement
showed no differences.21

2) Predictors of treatment response with clozapine

Since clozapine is the mainstay for the treatment
of RS, we will summarize its main predictors of response. The reader is also
referred to an excellent review published by Chung and Remington on this subject.22

A number of authors investigated the factors
associated with response to clozapine in cohort studies and found that high
levels of psychopathology, female gender, age at early onset of the disorder
and years of schooling, all to be predicted good response.23 Other
authors however, have obtained opposite results finding that patients who displayed
low levels of psychopathologic at baseline, as well as less severe negative
and extra-pyramidal symptoms, were the best responders.24

Doses of 300-600 mg/day are generally needed
to achieve the plasma threshold for response.22 Although studies
are not unanimous, plasma levels equal to or greater than 350 hg/ml
reaching 500 hg/ml tend to be associated with a satisfactory
clinical response. Caution is in order since these levels are lowered by nicotine.22
However, Potkin et al. observed that around 30% of non-responders achieved plasma
levels above the supposed adequate threshold.25

Genetic variants due to polymorphisms of dopaminergic
receptors D2, D3 and D4 have been described which influence the response to
clozapine, with the same occurring for genetic variants of serotoninergic receptors
5HT2a, 5HT2c and 5HT6.26 Glutamate and norepinephrine receptors were
also investigated,22 and recently the metabolic activity of the prefrontal
cortex of patients responsive to clozapine has been shown to be associated with
alleles of the D1 receptor.27 Nevertheless, as reviewed by Chung
and Remington, the available data on the genetic predictors of treatment response
to clozapine are presently inconsistent.22

The prefrontal region has been shown to have
an important role in the mediation of treatment response to atypical antipsychotics.
It is noteworthy that in the case of clozapine, 3 CT studies28-30
all found that an increased prefrontal sulcal prominence was associated with
a lesser response. However, another CT study31 and an MRI study32
found no relationship between prefrontal atrophy and treatment response to clozapine.
One of the most consistent findings was the reduction of the caudate in patients
taking clozapine when compared with patients who received FGA.33

Functional studies using Single Photon Emission
Tomography (SPECT)34 have observed an association between reduction
of metabolic activity in prefrontal regions and clozapine response. However,
a study by Chen et al. showed results in the opposite direction, i.e. increase
prefrontal activity and clozapine response.35 As previously mentioned,
a later study of the same author found an association between reduction of metabolism
in various brain areas and response to clozapine in patients homozygotes for
2.2 DRD1 gene, while no such reduction was found in non-responders homozygotes
for 1.2 DRD1.27

3) Treatment with non-clozapine antipsychotics

With advent of clozapine in 1988,12
which became the gold standard for the treatment of RS, other SGA (mainly risperidone,
olanzapine, quetiapine, ziprasidone) were tested for RS through various clinical
trials.2

Two famous meta-analyses showed opposite results
in terms of the efficacy of SGA over FGA. In one of these studies, Geddes et
al. found that the superiority of FGA is related to the dose of the comparator,
i.e. when the dose was < 12 mg of haloperidol SGA had no superiority
over FGA in terms of efficacy and tolerability.36 Some of the studies
of this meta-analysis involved controlled trials with RS patients treated with
clozapine, but no specific conclusion on this item was reported.

Davis et al. challenged these results with another
meta-analysis37 where clozapine showed almost twice the effect size
(0.49) in comparison with some others SGA (amisulpride = 0.29, risperidone =
0.25, olanzapine = 0.21). The effect size obtained for clozapine is due to studies
involving RS populations but also in this meta-analysis the authors haven't
acknowledged this issue.

Differently from randomized controlled trials,
pragmatic or practical trials are designed to measure effectiveness in a real-world
setting and population in order to provide the more complete information for
practice physician. A recent important pragmatic trial supports the evidence
of the effectiveness of clozapine over SGA for the treatment of schizophrenia.
As part of phase 2 of the CATIE study38  which involved about 1400
patients  Mc Evoy et al.39 studied 99 patients who haven't responded
to atypical antipsychotics in previous phases of the CATIE due to lack of efficacy.40
Patients were then assigned randomly to open label clozapine (n = 49) or blinded
treatment with another SGA (olanzapine n = 19; quetiapine n = 15; risperidone
n = 16). As results were compared to others SGA, clozapine showed to have greater
reductions in the PANSS total score, as well as the lowest discontinuation rates,
i.e. the use of clozapine proved to be more effective than switching to another
SGA in patients who have previously not responded to another SGA.

4) Polypharmacy with SGA

Polypharmacy in schizophrenia is widespread all
over the world41 despite the fact that there is no evidence of the
superiority of this empiricist therapeutic habit over monotherapy. Some consider
that combinations of SGA are well tolerated and may be effective for the treatment
of RS, while other authors remain more cautious due a lack of well-controlled
studies42 or evidence of harm as, for example, increased mortality.43
In a naturalistic study in seven psychiatric hospitals, Janssen et al.44
found that patients discharged with more than one antipsychotic had significantly
poorer outcomes with respect to both mental state and social functioning, while
Suzuki et al.41 observed an improvement when patients under antipsychotic
polytherapy were switched to monotherapy.

5) Clozapine polypharmacy

An incomplete response to clozapine is the persistence
of psychotic symptoms despite a trial of clozapine with adequate doses (i.e.
300-900 mg/day) during a minimum of 8 weeks up to 6 months. Thus, the improvement
of psychotic symptoms is considered the main treatment target and, as an apparent
logical consequence, it has been proposed the addiction of high potency antipsychotics
to clozapine for the treatment of these symptoms.

It is estimated that approximately 30% of patients
treated with clozapine do not respond adequately, remaining with persistent
psychotic symptomatology, despite having received adequate treatment for sufficient
periods. Such patients are called "partial responders to clozapine",
"clozapine resistant" or even "super-refractory", and represent
a challenge for the treatment of RS, as well as a great economic burden.44

The treatment of these patients is problematic
and pharmacological and non-pharmacological augmentation strategies remain the
only options for this population, despite the lack of adequate evidence for
efficacy.45,46 Many reviews have been published describing in detail
such strategies45,47 that will be summarized.

Various antipsychotics were used supposedly to
augment the antipsychotic properties of clozapine: amisulpride, aripiprazole,
haloperidol, loxapine, olanzapine, pimozide, and ziprasidone. The benefits of
these augmentation strategies remain inconclusive since they were tested in
case series or case reports, which have a low strength of evidence, as compared
with controlled trials.47

More robust evidence is derived from four placebo
controlled trials, one with sulpiride48 and three with risperidone49-51
and, due to their importance, they are summarized below. Shiloh et al. showed
a significant improvement on positive and negative symptoms in the group that
received sulpiride added to clozapine when compared with placebo group, and
it was proposed that this effect could be explained by the selective enhancement
of D2 blockage by sulpiride.48

However, it is well known that risperidone has
a strong affinity for D2 receptors and the hypothesis that blocking these receptors
would improve persistent positive symptoms in patients resistant to clozapine
was only supported by the Josiassen et al.'s study,49 but not by
Anil Yagcioglu or Honer's studies, since both studies found no differences between
risperidone or placebo groups.50,51

Therefore, the hypothesis that adding a more
potent antipsychotic to enhance or optimize D2 affinity, and thus improving
psychotic symptoms in poor clozapine responders, was not supported by the previous
studies, and it is also interesting to point out that in the Anil Yagcioglu
et al.'s study the placebo group showed a greater reduction in the PANSS positive
scores than the risperidone group.50

Finally, when clozapine augmentation with antipsychotics
fails, it has been proposed to switch to another antipsychotic. This strategy
is considered to have a weak level of evidence46 and olanzapine was
the antipsychotic most frequently tested in some open trials.52

Considering that suicide may represent an important
outcome dimension of RS, it is important to mention the results of the International
Suicide Prevention Trial (InterSePT)53 of 2-year duration where 980
patients with schizophrenia (about 260 with RS), recruited from 67 medical centers
in 11 countries, were randomized either for clozapine or olanzapine. Results
showed that compared to olanzapine, patients taking clozapine had significantly
reduced rates of suicidal behavior or suicide attempts, while the rates of deaths
due to suicide were not statistically different between groups. A Number Needed
to Treat (NNT) equals 13 was obtained, showing that for every 13 high-risk patients
treated, one less patient will have suicide events if they were treated with
clozapine rather than olanzapine.

6. Non-pharmacological treatments

1) ECT and TMS

Despite the fact that ECT is recommend as an
augmentation strategy for clozapine non-responders in some guidelines13
or algorithms such as the TMAP14 or the IPAP (www.ipap.org),
there only few studies providing evidence of efficacy for this intervention.54

Despite the fact that Transmagnetic Cranial Stimulation
(TMS) has been used for the treatment of medication-resistant auditory hallucinations
in controlled studies, only recently Rosa et al. tested TMS in the first controlled
study for clozapine non-responders as compared with placebo ("sham")
and found that TMS can be administered safely for patients taking clozapine,
although the authors couldn't find a significant difference between the groups
due to the lack of power of the study (active TMS = 6 patients; Sham: 5 patients).55

2) Cognitive behavior therapy

Cognitive behavioral therapy (CBT) has been extensively
used in patients refractory to antipsychotics, but only few studies included
patients resistant to clozapine,56 showing that this technique can
help them to control their symptoms, especially hallucinations. We presented
preliminary data showing that CBT in severe patients resistant to clozapine
can also improve general psychopathology and quality of life.57